Minimally invasive surgical techniques have revolutionized cardiac surgery. Minimally invasive cardiac surgery enjoys the advantages of reduced morbidity, quicker recovery times, and improved cosmesis over conventional open-chest cardiac surgery. Recent advances in endoscopic instruments and percutaneous access to a patient's thoracic cavity have made minimally invasive surgery possible. Reduction in morbidity, lower cost, and reduced trauma has made minimally invasive surgery desirable.
One approach to minimally invasive cardiac surgery is coronary artery bypass grafting ("CABG") on a beating heart. At present, safe, reproducible, and precise anastomosis between a stenotic coronary artery and a bypass graft vessel presents numerous obstacles including myocardial ischemia (or arrhythmia induced by the transient period of coronary artery occlusion necessary for coronary arrest), significant bleeding into the operative field from septal bleeders despite adequate epicardial coronary artery occlusion, inability to graft the left circumflex system due to hemodynamic sequelae induced by lifting the heart, and continuous cardiac translational motion which may impair meticulous microsurgical placement of graft sutures.
For CABG on a beating heart to be universally accepted, the superior patency rates of the internal thoracic artery to the left anterior descending artery (LAD) can not be compromised. A major obstacle to safe and precise coronary anastomosis is the constant motion of the beating heart. Surgical approaches have been developed to stabilize the heart and facilitate anastomosis. Most new approaches employ some form of mechanical stabilization to stabilize the beating heart, such as the "fork-shaped" coronary artery stabilizer manufactured by Cardio Thoracic Systems, Inc. and described in Boonstra, P. W., Grandjean J. G., Mariani, M. A., Improved Method for Direct Coronary Grafting Without CPB Via Anterolateral Small Thoracotomy, Ann. Thorac. Surg. 1997;63:567-9. The coronary artery stabilizer in combination with an access platform in which it sits helps stabilize the left anterior descending artery on the beating heart and permits an arteriotomy with a conventional scalpel and scissors. In addition, many other different technologies that allow local coronary wall immobilization have been developed including various platform devices and the Utrecht "Octopus" device in which suction pods are placed adjacent the coronary artery. The suction immobilization simulates the arrested condition locally (see, e.g., Borst C., Jansen E. W. L., Tulleken C. A. F., et al., Coronary Artery Bypass Grafting Without Cardiopulmonary Bypass and Without Interruption of Native Coronary Flow Using a Novel Anastomosis Site Restraining Device ("Octopus"), J. Am. Coll. Cardiol. 1996;27:1356-64).
However, precise vascular anastomosis using mechanical stabilization techniques remains elusive due in large part to the inherent difficulties in maintaining uniform and steady pressure on opposite sides of the LAD. Moreover, the constant translational motion of the heart and bleeding from the opening in the coronary artery hinder precise suture placement in the often tiny coronary vessel. Although bleeding can be reduced by using proximal and distal coronary occluders, by excluding diagonal and septal branches near the arterial opening when possible, and by continuous saline irrigation or humidified carbon dioxide insufflation, the incessant motion of the beating heart remains the Achilles' heel of minimally invasive coronary artery bypass surgery.
In response to problems associated with mechanical stabilization techniques, a new technique has been developed to minimize the cardiac motion which employs a novel pharmaceutical approach to stabilizing the heart. This revolutionary pharmaceutical approach to cardiac stabilization is described in co-pending provisional patent application Ser. No. 60/055,127 for Compositions, Apparatus and Methods For Facilitating Surgical Procedures, filed Aug. 8, 1997 and invented by Francis G. Duhaylongsod. M.D, the entire contents of which are expressly incorporated by reference herein. As described therein, pharmaceutical compositions and methods are provided which are useful for medical and surgical procedures which require precise control of cardiac contraction, such as coronary artery bypass procedures. In a preferred embodiment of that invention, a pharmaceutical composition is provided that is capable of inducing reversible ventricular asystole in a patient, while maintaining the ability of the heart to be electrically paced. "Reversible ventricular asystole" refers to a state wherein autonomous electrical conduction and escape rhythms in the ventricle are suppressed. A state of the heart may be induced wherein the heart is temporarily slowed to at least about 25 beats per minute or less, and often about 12 beats per minute or less. The induced ventricular asystole is reversible and after reversal, the heart functions are restored, and the heart is capable of continuing autonomous function.
The pharmaceutical composition may include, for example, an atrioventricular ("AV") node blocker and a beta blocker. As used herein, the term "AV node blocker" refers to a compound capable of reversibly suppressing autonomous electrical conduction at the AV node, while still allowing the heart to be electrically paced to maintain cardiac output. Preferably, the AV node blocker, or the composition comprising the AV node blocker, reduces or blocks ventricular escape beats and cardiac impulse transmission at the AV node of the heart, while the effect on depolarization of the pacemaker cells of the heart is minimal or nonexistent. The beta blocker is provided in one embodiment in an amount sufficient to substantially reduce the amount of AV node blocker required to induce ventricular asystole. For example, the AV node blocker may be present in the composition in an amount which is 50% or less by weight, or optionally about 1 to 20% by weight of the amount of AV node blocker alone required to induce ventricular asystole.
The pharmaceutical composition, such as an AV node blocker, capable of causing ventricular asystole in a preferred embodiment is a cholingeric agent such as carbachol, although other cholingeric agents may be used as well. In the preferred embodiment, the beta blocker is propranolol, although other suitable beta blockers may be used as well. The administration of the beta blocker is preferably prior to, or contemporaneously with, the administration of the cholinergic agent, and results in a synergistic effect between the beta blocker and the cholinergic agent. The use of a cholinergic agent, such as carbachol, in combination with a beta-blocker, such as propranolol, produces ventricular asystole at significantly reduced dosages of the cholinergic agent, while maintaining a short half-life and rapid onset of effect.
The cholinergic agent, such as carbachol, is generally administered in an initial intracoronary bolus of about 5 to 150 .mu.g/kg body weight of patient, or about 2 to 20 .mu.g/kg body weight of patient, for example, about 4 to 16 .mu.g/kg, or about 6 to 14 .mu.g/kg, or in one embodiment, about 8 to 12 .mu.g/kg body weight, in a suitable pharmaceutically acceptable carrier or diluent. The bolus infusion of the cholinergic agent is preferably followed by a continuous infusion of the cholinergic agent. The infusion rate is generally about 0.1-4.8 .mu.g/kg body weight patient/min, preferably about 0.1-1.2 .mu.g/kg/min, or about 0.1-1.0 .mu.g/kg/min. A typical total adult dosage of the cholinergic agent, such as carbachol, is about 1 mg to 15 mg for a 120 min period of ventricular asystole. The dosage may be adjusted depending on the surgical procedure. The beta blocker, such as propranolol, is typically administered in a single bolus in a dosage amount of about 0.01 to 0.07 mg/kg body weight of patient, for example about 0.01 to 0.05 mg/kg, or about 0.01 to 0.04 mg/kg. The total amount of propranolol administered is typically about 1 mg to 5 mg, for example about 2 to 4 mg, or about 3 mg.
As described above, the combination of AV node blocking using an effective dosage amount of an AV node blocker (such as carbachol), and/or other means of stimulating the AV node such as vagal nerve stimulation, in combination with an effective dosage amount of a beta blocker (such as propranolol) produces precise and controlled prolonged periods of reversible ventricular asystole of the heart while maintaining the ability of the heart to be electrically paced. Electrical pacing wires are connected to the right ventricle and or left ventricle and are used to pace the heart to maintain the patient's blood circulation during the periods in which the surgeon is temporarily not performing the surgical procedure. Thus, for example, in a CABG procedure, the surgeon can control the pacing of the heart with a convenient foot pedal and can controllably stop the heart as sutures are placed in the vessel walls. The pharmaceutical compositions and methods described above give a surgeon complete control of the beating heart.
For the pharmaceutical compositions described above to be most effective, those pharmaceutical compositions must be precisely delivered to the AV node of the heart upon which they act, preferably by way of the AV nodal branch artery of the heart. New surgical devices and methods are required to allow the surgeon to reliably and easily deliver such pharmaceutical compositions or other drugs or fluids to the heart or other major organ directly via the internal lumen of a coronary vessel. In particular, an intraluminal shunt apparatus is needed which can be easily inserted directly into an incision in a coronary vessel which delivers blood to or drains blood from the AV nodal branch artery, such as the right coronary artery, the posterior descending vein, the left circumflex, or the AV nodal branch artery itself. Direct access to the internal lumen of a vessel via an intraluminal shunt has a number of advantages. First, the intraluminal shunt may be easily employed by the cardiac surgeon under direct or endoscopic visualization without the need for x-ray fluoroscopy, which is often not present in most operating rooms. Moreover, surgeons are not very facile with drug delivery catheters delivered through a percutaneous approach, and the use of an intraluminal shunt obviates the need for a femoral or brachial arterial puncture needed for placement of a drug delivery catheter in a vessel.
Presently, intraluminal shunts are employed by surgeons to reduce intraoperative ischemia and facilitate the construction of coronary artery bypass grafts. For example, the Rivetti-Levinson.TM. intraluminal shunt (from Heyer-Schulte NeuroCare Group) (patent pending) employs a standard T or L-shaped intraluminal shunt having a main shunt body which is configured to be inserted into a coronary artery vessel and which provides direct or passive perfusion of the distal coronary arterial lumen during construction of coronary bypass grafts in the non-arrested heart. A side port is provided to actively perfuse the coronary artery from a secondary source using a standard luer connection. However, this device is specifically not designed or intended for drug administration into the coronary artery vessel.
U.S. Pat. No. 5,695,504 to Gifford et al. discloses a catheter device for isolating a section of a coronary artery while performing a distal anastomosis. The catheter device includes a T-shaped distal portion which includes a single dedicated blood and/or fluid delivery lumen which allows blood to flow through the device downstream from the anastomosis site. A single side perfusion limb is provided which is in fluid communication with the main perfusion lumen for infusing blood and/or cardioplegia solution into the catheter if the passive blood flow through the main perfusion lumen is insufficient because of a severe stenosis or total occlusion upstream of the anastomosis site.
In light of the foregoing, it is desirable to provide an intraluminal shunt apparatus that can be used to quickly and easily deliver a drug and/or other fluid to the vessel of a patient undergoing a surgical procedure, such as a CABG procedure, while also maintaining either passive or active blood perfusion through the vessel. It would be further desirable to provide such a device that could be used in minimally invasive cardiac surgery procedures (or open-chest surgical procedures) to deliver a pharmaceutical composition to the heart of a patient that is capable of inducing temporary reversible ventricular asystole of the heart while maintaining the ability of the heart to be electrically paced. Preferably, the intraluminal shunt should be configured to be inserted into a target vessel that delivers blood to or drains blood from the AV nodal branch artery of the heart, such as the right coronary artery, the posterior descending vein, the left circumflex, or the AV nodal branch artery itself In this way, the pharmaceutical compositions described above, for example, which act in part on the AV node, can be effectively administered locally to the heart in either a bolus injection or a continuous infusion to provide temporary periods of cardiac standstill.
Further, it would be desirable to provide an intraluminal shunt apparatus which is configured to permit the delivery of the pharmaceutical composition or other fluid in either an anterograde direction (forward direction which is the same direction as normal blood flow through the vessel) or a retrograde direction (reverse direction which is opposite to the direction of normal blood flow through the vessel) through the intraluminal shunt and the coronary vessel. This is particularly important where the surgeon does not have the advantage of x-ray fluoroscopy to precisely position the shunt device at a desired position within a target vessel. Thus, the intraluminal shunt apparatus should provide the surgeon with the capability to deliver the drug or fluid in either an anterograde or retrograde direction depending on whether the shunt apparatus is placed in the target vessel upstream or downstream from the position to which it is desired to deliver the drugs or other fluids.
If would be further desirable to have an intraluminal shunt with sufficient flexibility so that it can be easily inserted into and removed from the target vessel. In addition, the device preferably should also permit mixing of the drug or fluid with the blood perfusing through the device to enhance the effectiveness of the drug or fluid at its target location.